Parkinson's disease and its resistance to treatment

Parkinson’s disease is defined as the deterioration of the central nervous system. It is a deep rooted illness which impacts the motor function of the body. The symptoms are slow to disclose as they take a longer period of time to reveal. The source, root cause of Parkinson’s disease is yet to be known, but there is a strong conviction that the causes might be related to hereditary and environmental factors of an individual.

Presently, Parkinson’s disease has no known treatment for cure, but there are medications that can improve the patient’s symptoms. L.DOPA medication, previously used in the treatment of Parkinson’s disease became inefficient due to sustained loss of neurons over time apart from presenting complications such as involuntary writhing in patients.

A number of alternative treatments have emerged based on the ineffectiveness of earlier treatments. For example, gene therapy is one of the alternative treatments which uses a non-infectious virus which breaks down the genetic material in some part of the brain. This then results into the release of an enzyme which gradually manages the symptoms of Parkinson’s disease. More damage to the brain is also minimized through this form of treatment. Gene therapy also helps to rectify the imbalance in ganglia circulatory system.

Progenitor cell therapy gives room for development of huge amount of specific cells used in the therapeutic process.

This allows for analysis of the cells in terms of their composition and dosage to be applied so as to yield the most benefit to the victims of this disease.

Both treatment methods present promising results that will enhance the capacity for structural and cellular modification of the brain.

Cell Therapy

The use of cell replacement therapy on the brain of patients of Parkinson disease helps to restore the neural system functions as well as dopaminergic (DA). Experiments that have been conducted show that deficiencies in the motor function as a result of Parkinson’s disease are significantly reduced with the use of this method of treatment.

Inferences from the tests that have been conducted show that the disease does not harm any of the transplanted fetal dopaminergic (DA) cells even as the patient’s original DA system degenerates further. Transplants that contain neurons from the midbrain exhibits functionality for almost 10 years on average from the tests conducted so far. In addition, there is survival of neurons and graft with no need for pathology to be done after surgery for as long as 14 years later.

Based on the huge effort that has been applied in creating an understanding of the biological factors that are at play, there exists potential for cell therapy to be used in treatment of Parkinson’s disease. Despite the promises and proven cases of success that this technology offers in the treatment of Parkinson’s disease, there is much more sophistication involved in the treatment in terms of the cellular, biological and technical aspects which will make such treatments safe for patients and reliable enough.

The major challenge with this new technology is being able to optimize the functional effects as well as limiting the side effects of the treatment by making available the appropriate release of DA while maintaining connection to the nigrostriatal system. Fetal DA neurons that have been transplanted has been seen to establish synaptic contact with striatal neurons.

Ongoing research indicate that regulation of the striatal neurons together with network interaction which is DA mediated is crucial for motor function.

When this release of the DA is unregulated the glutamatergic synapses are incapable of providing sufficient GABA output neurons.

Transplants of the DA has exhibited that it has the ability to reduce dyskinesias that is caused by L-DOPA among the primates.

In several instances when fetal mesencephalic cells have been transplanted, it has been reported that patients suffering from Parkinson’s disease were able to do away with their medications of DA. The major challenge with this is that knowledge on the process of patient selection and the factors involved in the cell transfer is insufficient despite confirmed results of transplant survival for several years even up to 15 years in some cases. Furthermore, the transplants that have been done in several countries present mixed results with some patients reporting success of the treatment while others showing negative results after the transplants.

Advanced studies into this new technology show that DA cells implantation displays a wide range of effects from mild to severe ones among the patients. The key issue is the emergence of off-medication type of dyskinesias among some patient whose DA grafts have exhibited quite a good survival. This phenomenon is unknown to many researchers and the mechanism of its operation is also unknown.

Some studies however show that despite the graft viability being good, the host suboptimally reinnervert the target areas as well as the composition of the DA cells of the grafts that have survived and those that have been transplanted. In some cases, the transplanted neurons release a lot of DA for denervated striatum resulting in dyskinesia on off moments.

In addition, there is a risk of adverse effect as well as dyskinesia which relies upon the position and size of the transplant since lesions of the posterior putamen produces dyskinesias when it is exposed to DA.

Some studies suggest that the level of advancement and the response to L-DOPA treatment greatly impacts the results of the transplant process together with the new DA cells function. This demonstrates that level of extremeness of Parkinson’s disease has a direct impact on the transplant.

Statistically those patients with less than 50 points according to Unified Parkinson’s Disease Rating Scale (UPDRS) present much better results or response to fetal transplants in comparison to patients who undergo placebo operation. On the other hand, patients with advanced level of Parkinson’s disease, that is, more than 50 points on the UPDRS do not have promising results.

In order for treatment for Parkinson’s disease using cell therapy to be much more promising than the current results, there is need to select patients who are more responsive to earlier forms of treatment and also to use neurons that are more appropriate to the transplant in order for the treatments to be successful.

This will only be possible if there is sufficient information in the form of knowledge on the appropriate use of the right procedure and surgery that will yield optimal results ultimately. It will also be appropriate to know the right location for cell implantation and the right amount of cell dosage to use in the cell therapy. It is also of crucial importance to prepare the cells and take into account the trophic factors that may impact on the cell therapy.

It is also deemed necessary to factor in the connectivity and immunological factors so as to enable functionality in the reconstitution of the neuro-circuit. This means that for the treatment of Parkinson’s disease to be successful, properly selected and appropriate DA neurons need to be given to patients who are responsive to cell therapy. With advancement in the techniques and surgery alongside the use of stem-cell DA neurons offers a much more robust substitution cell therapy to patients.

Gene Therapy

Gene therapy basically refers to the use of viral encoding for a particular protein to insert DNA into the host cell.

Use of therapeutic proteins always has its main purpose being the prevention of the degeneration of the host’s system, ensuring the arrangement of the synapses is strong enough as well enhancing the phenotype of the DA.

In the attempt to provide a substitute therapy, many attempts have been made to alter the neural circuitry of the host as well as use of enzymes to boost the production of DA. This also helps to increase the effectiveness of L-DOPA and also transportation of inhibitory transmitter enzyme which basically reverses extremely active sites in the brain inside the basal ganglia circuitry as well as the transportation of the trophic factors to the CNS.

With regards to trophic factors, it is visible that such proteins protect neural cells which are vulnerable to Parkinson’s disease which will lead to degeneration and augmentation of the phenotype of DA in the nigrostriatal system of the host. The major challenge with such treatment is that it is difficult to determine appropriate trophic factors which will sustain the nigrostriatal system of the host. Another challenge with this new technology is that it is difficult to efficiently and effectively dispense the trophic factors.

Initially viral vectors were used to imitate the production of L-DOPA in cells but it was ceased in later years because it caused inflammation sensation in test subjects. To solve this problem, modifications have been made to HSV and Ad-based vectors so as make them safer and efficient in the expression of transgene.

Trophic factors present the potential of providing neuroprotection and cell restoration in the host. It is important to note that the type of viral vector that is used in the delivery of neurotrophic factor will determine the amount of the trophic molecules in the DNA. The type of viral vector also influences the type of procedure and surgical application. For instance, appropriate surgical procedure is needed in cases that require deep brain simulation.

Non-viral application is not as complex as the other method which requires the modification of viral vectors but are less effective in treating Parkinson’s disease which is a long term neuro degenerative disorder since such alternatives have a shorter time lapse of gene expression.

This short time of gene expression in non-viral vectors poses a risk in human trials since this would mean that the brain would be subjected to numerous injections after every short while in order to realize any meaningful response posing a great risk of brain injury to the patients.

Obtaining viral vectors from RNA or DNA is a more feasible option since it has the potential to produce durable gene expression through formation of episome or integration of the DNA into the genome of the host.

A number of factors need to be considered so as to make gene therapy safe and ready for human use. An understanding of the complex pathophysiology of Parkinson’s disease is crucial in the selection of the appropriate therapeutic target in terms of the pathways of signaling and the complex brain structures.

In the selection of the therapeutic target, there are three approaches. One, there needs to be increase of dopamine in the basal ganglia through the use of transgene encoding enzyme. The main enzyme in the dopamine metabolism are GTP-cyclohydrolase -1 (GCH-1), tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC). Second, increase of GABA to remedy the hyper activity in the subthalamic nucleus so as to modulate the basal ganglia circuitry. Third, prevention of the death of the dopaminergic neurons through the use of neurotrophic factors such as glial-cell, neurturin and brain derived neurotrophic factors.

AADC produces dopamine from endogenous levodopa so as to manage the symptoms of Parkinson’s disease as it progresses. Increase of this enzyme in the gene therapy has exhibited potential of reducing the symptoms of Parkinson’s disease, the quantity of levodopa required to manage the symptoms and also improving the side effects of continuous use of levodopa.

The information obtained from laboratory trials of gene therapy for persons suffering from Parkinson’s disease exhibits mixed results on the motor system of the patients.

Treatment of Parkinson’s disease through the use of gene therapy has over the year’s undergone huge sophistication. Such advancements in this new technology have assisted scientists in remedying difficulties of targeting degenerative cells in patients and being able to avoid incidences of neurotoxicity of molecular targets.

The potential of gene therapy being used to treat Parkinson’s disease and other neurological disorders is an achievable goal and may be realized with concerted effort being placed on more research in this particular field of study.

References

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J. L. Eberling, W. J. Jagust, C. W. Christine et al. "Results from a phase I safety trial of hAADC gene therapy for Parkinson disease." Neurology (2008): 1980-1983.

P. Brown, A. Oliviero, P. Mazzone, A. Insola, P. Tonali, and V. Di Lazzaro,. "Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson's disease." Journal of Neuroscience (2001): 1033-1038.